Caraccio N, Dardano A, Manfredonia F, Manca L, Pasquali L, Iudice A, Murri L, Ferrannini E, Monzani F
J Clin Endocrinol Metab 2005 Jul;90(7):4133-7
University of Pisa, Department of Internal Medicine and Department of NeuroScience, Pisa, Italy
Conflicting data have been reported on the association between IFN-ß therapy of Multiple Sclerosis (MS) patients and Thyroid Disease development.
- To assess the actual occurrence of Thyroid dysfunction and Autoimmunity during long-term IFN-ß therapy
- To establish the possible presence of predictive factors for Thyroid dysfunction development and duration
- To suggest an effective follow-up protocol for patients receiving long-term IFN-ß therapy
Study protocol 106 MS patients (76 women) underwent IFN-ß 1a or 1b therapy for up to 84 months (median 42).
Thyroid function and AutoImmunity were assessed at baseline and every 3-6 months throughout the treatment course.
Baseline Thyroid AutoImmunity was detected in 8.5% of patients and HypoThyroidism in 2.8%.
Thyroid Dysfunction (80% HypoThyroidism, 92% subclinical, 56% transient) developed in 24% (68% with AutoImmunity) of patients and AutoImmunity in 22.7% (45.5% with dysfunction), without significant differences between the two Cytokines; 68% of dysfunctions occurred within the first year.
AutoImmunity emerged as the only predictive factor for dysfunction development (RR 8.9), while sustained disease was significantly associated with male gender (P < 0.003).
Both incident Thyroid AutoImmunity and dysfunction frequently occur in MS patients during IFN-ß therapy, particularly within the first year of treatment.
Thyroid dysfunction is generally subclinical and transient in over than half of cases; preexisting or incident AutoImmunity emerged as the only significant predictive factor for Thyroid dysfunction development.
Thyroid function and AutoImmunity assessment is mandatory within the first year of IFN-ß therapy thereafter, serum TSH measurement only in patients with Thyroid Disease could be sufficient.
Druzhyna NM, Musiyenko SI, Wilson GL, Ledoux SP
J Biol Chem 2005 Jun 3;280(22):21673-9
University of South Alabama, Department of Cell Biology and NeuroScience, Mobile, AL 36688-0002
Nitric Oxide (NO) that is produced by inducible NO Synthase (iNOS) in Glial Cells is thought to contribute significantly to the pathogenesis of Multiple Sclerosis (MS).
Oligodendrocytes can be stimulated to express iNOS by Inflammatory Cytokines which are known to accumulate in the MS Brain.
The potentially pathological levels of NO produced under these circumstances can target a wide spectrum of IntraCellular components.
We hypothesized one of the critical targets for damage that leads to disease is Mitochondrial DNA (mtDNA).
In this study, we found that Cytokines, in particular a combination of TNF- (50ng/ml) and IFN (25ng/ml), cause elevated NO production in primary cultures of rat Oligodendrocytes.
Western blot analysis revealed a strong enhancement of iNOS expression 48 h after Cytokine treatment.
Within the same time period, NO-mediated mtDNA damage was shown by Southern blot analysis and by ligation mediated PCR.
Targeting the DNA repair Enzyme 8-OxoGuanine Glycosylase (hOGG1) to Mitochondria of Oligodendrocytes had a protective effect against this Cytokine-mediated mtDNA damage.
Moreover, studies using a TUNEL assay showed that MTS-hOGG1 transfected Oligodendrocytes had fewer Apoptotic Cells (17%+/-5.2) compared to cells containing vector only (31%+/-3.6) following treatment with the Cytokines.
Subsequent experiments revealed that targeting hOGG1 to Mitochondria reduces the activation of caspase 9 showing that this recombinant protein works to reduce Apoptosis that is occurring through a Mitochondrial based pathway.
CD163-Positive Perivascular Macrophages In The Human CNS Express Molecules For Antigen Recognition And Presentation
Fabriek BO, Van Haastert ES, Galea I, Polfliet MM, Dopp ED, Van Den Heuvel MM, Van Den Berg TK, De Groot CJ, Van Der Valk P, Dijkstra CD
Glia 2005 Apr 21
VU Medical Center, Department of Molecular Cell Biology and Immunology, Amsterdam, the Netherlands
PeriVascular Macrophages (PVM) constitute a subpopulation of resident Macrophages in the Central Nervous System (CNS) that by virtue of their strategic location at the Blood-Brain Barrier potentially lend themselves to a variety of important functions in both health and disease.
Functional evidence suggests that PVM play a supportive role during Experimental Autoimmune Encephalomyelitis in rodents. However, the function of PVM in the human CNS remains poorly characterized.
We first set out to investigate the validity of the AntiBody EDhu1, which recognizes human CD163, to specifically identify human PVM.
Second, we wanted to gain insight into the function of PVM in Antigen recognition and presentation and therefore we studied the expression of DC-SIGN, Mannose Receptor, MHC Class II.
And, several costimulatory molecules by PVM in the normal and inflamed human CNS (Multiple Sclerosis (MS) Brain lesions).
Conventional ImmunoHistoChemistry and double-labeled ImmunoFluorescence techniques were used. We show that CD163 specifically reveals PVM in the normal human CNS.
In MS lesions, CD163 staining reveals expression on foamy Macrophages and Microglia, besides an upregulation of the amount of PVM stained.
In contrast, Mannose Receptor expression is restricted to PVM in both normal and inflamed Brain tissue.
Furthermore, we show that a subpopulation of PVM in the human Brain express several molecules involved in Antigen recognition, presentation, and costimulation.
Therefore PVM, which occupy a strategic location at the BBB, are equipped to recognize Antigen and present it to T-Cells, supporting a role in the regulation of PeriVascular inflammation in the human CNS.
(c) 2005 Wiley-Liss, Inc.
Lipoic Acid In Multiple Sclerosis: A Pilot Study
Yadav V, Marracci G, Lovera J, Woodward W, Bogardus K, Marquardt W, Shinto L, Morris C, Bourdette D
Mult Scler 2005 Apr;11(2):159-65
Department of Veterans Affairs Medical Center, Portland, OR, USA
Lipoic Acid (LA) is an antioxidant that suppresses and treats an animal model of Multiple Sclerosis (MS), Experimental Autoimmune Encephalomyelitis.
The purpose of this study was to determine the PharmacoKinetics (PK), tolerability and effects on Matrix Metalloproteinase-9 (MMP-9) and soluble InterCellular Adhesion Molecule-1 (sICAMP-1) of oral LA in patients with MS.
Thirty-seven MS subjects were randomly assigned to one of four groups: placebo, LA 600 mg twice a day, LA 1200 mg once a day and LA 1200 mg twice a day.
Subjects took study capsules for 14 days. We found that subjects taking 1200 mg LA had substantially higher peak Serum LA levels than those taking 600 mg and that peak levels varied considerably among subjects.
We also found a significant negative correlation between peak Serum LA levels and mean changes in Serum MMP-9 levels (T = -0.263, P =0.04).
There was a significant dose response relationship between LA and mean change in Serum sICAM-1 levels (P =0.03).
We conclude that oral LA is generally well tolerated and appears capable of reducing Serum MMP-9 and sICAM-1 levels.
LA may prove useful in treating MS by inhibiting MMP-9 activity and interfering with T-Cell migration into the CNS.
Functional Outcome Of Intrathecal Baclofen Administration For Severe Spasticity
Boviatsis EJ, Kouyialis AT, Korfias S, Sakas DE
Clin Neurol NeuroSurg 2005 Jun;107(4):289-95
Evangelismos General Hospital, University of Athens Medical School, Department of NeuroSurgery, 61 Ipsilantou Street, Kolonaki, Athens 11521, Greece
To estimate the functional benefit in patients with severe Spasticity treated with Intrathecal Baclofen infusion through an implantable pump and to stress the need for functional assessment of these patients with a functional scale.
Patients And Methods
Between 1999 and 2003, 22 patients with a long history of severe and disabling pharmaceutically intractable Spasticity, underwent implantation of a pump for continuous Intrathecal Baclofen infusion.
The patients were subdivided into two categories according to the Etiology of Spasticity: 15 had Multiple Sclerosis and seven had suffered a Spinal Cord Injury at different levels (from C4 to T11).
Clinical status was assessed with the Ashworth and Penn spasm scales. Functional benefits were evaluated with the Barthel index score and pain relief with a self-reported visual analogue pain scale.
Postoperatively, all patients presented improvement in Spasticity, reduction of spasm frequency, significant improvement in functional status, enhancement of life comfort and reduction of pain.
Reduction of Spasticity and spasms achieved with intrathecally delivered Baclofen, leads to functional improvement and pain relief.
Arch Neurol 2005 May;62(5):714-7
University of Southern California School of Medicine, Department of Neurology, Los Angeles, CA 90033, USA
InterNuclear Ophthalmoplegia (INO) is a sign of exquisite localizing value, often due to either Multiple Sclerosis or infarction.
To demonstrate that unusual causes of INO are more common than the 11% reported in previous series, this review considers a case series of 410 inpatients whom I personally examined during a 33-year period.
In this series, the cause of INO was infarction in 157 patients (38%), Multiple Sclerosis in 139 (34%), and unusual causes in 114 (28%).
Unusual causes included Trauma (20 cases), Tentorial Herniation (20 cases), Infection (17 cases), Tumor (17 cases), Iatrogenic Injury (12 cases), Hemorrhage (13 cases), Vasculitis (7 cases), and Miscellaneous (8 cases).
InterNuclear Ophthalmoplegia was unilateral in 136 of the infarct cases (87%), 38 of those with Multiple Sclerosis (27%), and 48 of the unusual cases (42%).
Because unusual causes compose more than one quarter of the cases, the differential diagnosis of INO should be Tripartite: Multiple Sclerosis, Stroke, and Other Causes.
Soelberg Sorensen P, Koch-Henriksen N, Ross C, Clemmesen KM, Bendtzen K
Neurology 2005 Jul 12;65(1):33-9
From the Copenhagen MS Center, Department of Neurology (Dr. Sorensen), and Institute for Inflammation Research (Drs. Ross and Bendtzen), Copenhagen University Hospital, Rigshospitalet; and Department of Neurology, Aalborg Hospital, and The Danish MS Treatment Register (Dr. Koch-Henriksen), Denmark
Neutralizing AntiBodies (NABs) occur frequently in patients receiving Interferon-IFN (IFN-ß) for Multiple Sclerosis (MS), but it is unclear whether occurrence of NABs is predictive for the persistence of NABs during continued IFN-ß therapy.
The authors used an AntiViral Neutralization Bioassay to measure NABs blindly from 6 months up to 78 months in patients with MS who were followed for at least 24 months during treatment with IFN-ß.
Patients were classified into three groups:
- Persistently NAB-negative patients, defined as
- patients without any positive samples at any time
- Definitely NAB-positive patients, defined as
- patients who had at least two consecutive positive samples
- Patients with fluctuating NAB-positive and NAB-negative samples
A total of 455 patients were included in the study.
Overall, 52.3% of the patients were persistently NAB-negative, 40.9% became definitely NAB-positive, and the remaining 6.8% were fluctuating.
More patients treated with IFN-ß-1a (Avonex) remained NAB-negative (p < 0.0001), whereas there was no difference between IFN-ß-1b (Betaferon) and IFN-ß-1a (Rebif).
Patients who have remained NAB-negative during the first 24 months of therapy rarely developed NABs. On the contrary, the majority of patients, who had been NAB-positive from 12 through 30 months after start of therapy, remained NAB-positive.
NABs should be measured in all patients treated with IFN-ß. If patients have been persistently NAB-negative for 24 months, measurements can be discontinued.
Patients who have been NAB-positive for a period of 18 months or more usually remain NAB-positive for a long time.